chr21-37471158-A-G

Variant names:

• chr21-37471158-A-G
• rs10470178
• NM_001347721.2:c.11-1526A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001347721.2(DYRK1A):​c.11-1526A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 152,032 control chromosomes in the GnomAD database, including 6,741 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.30 (6741 hom., cov: 32)
• Consequence: DYRK1A NM_001347721.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• Publications: 2 publications found

Genes affected

DYRK1A (HGNC:3091): (dual specificity tyrosine phosphorylation regulated kinase 1A) This gene encodes a member of the Dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family. This member contains a nuclear targeting signal sequence, a protein kinase domain, a leucine zipper motif, and a highly conservative 13-consecutive-histidine repeat. It catalyzes its autophosphorylation on serine/threonine and tyrosine residues. It may play a significant role in a signaling pathway regulating cell proliferation and may be involved in brain development. This gene is a homolog of Drosophila mnb (minibrain) gene and rat Dyrk gene. It is localized in the Down syndrome critical region of chromosome 21, and is considered to be a strong candidate gene for learning defects associated with Down syndrome. Alternative splicing of this gene generates several transcript variants differing from each other either in the 5' UTR or in the 3' coding region. These variants encode at least five different isoforms. [provided by RefSeq, Jul 2008]

DYRK1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• DYRK1A-related intellectual disability syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347721.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	NM_001347721.2	MANE Select	c.11-1526A>G		intron	N/A	NP_001334650.1
	DYRK1A	NM_001396.5		c.11-1526A>G		intron	N/A	NP_001387.2
	DYRK1A	NM_001347722.2		c.11-1526A>G		intron	N/A	NP_001334651.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYRK1A	ENST00000647188.2	MANE Select	c.11-1526A>G		intron	N/A	ENSP00000494572.1
	DYRK1A	ENST00000398960.7	TSL:1	c.11-1526A>G		intron	N/A	ENSP00000381932.2
	DYRK1A	ENST00000338785.8	TSL:1	c.11-1526A>G		intron	N/A	ENSP00000342690.3

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44842 AN: 151916 Hom.: 6733 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.203

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.289

Gnomad OTH AF: 0.295

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.295 AC: 44873 AN: 152032 Hom.: 6741 Cov.: 32 AF XY: 0.298 AC XY: 22154 AN XY: 74316

African (AFR) AF: 0.292 AC: 12122 AN: 41468

American (AMR) AF: 0.267 AC: 4083 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.203 AC: 704 AN: 3472

East Asian (EAS) AF: 0.363 AC: 1875 AN: 5168

South Asian (SAS) AF: 0.379 AC: 1827 AN: 4820

European-Finnish (FIN) AF: 0.344 AC: 3624 AN: 10540

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.289 AC: 19662 AN: 67964

Other (OTH) AF: 0.300 AC: 633 AN: 2110

Alfa AF: 0.284 Hom.: 8229

Bravo AF: 0.290

Asia WGS AF: 0.376 AC: 1308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10470178; hg19: chr21-38843460;